Week 2: Neuronal Signaling Part 2

Serotonin

- AKA 5HT - Neuromodulator involved at virtually every structure in the brain and spinal cord - Operates via at least 16 different receptor subtypes - Has an excitatory effect on pathways that are in control of muscles - Inhibitory effect on pathways that mediate sensations - Made from essential amino acid tryptophan

Subtypes of ionotropic glutamate receptors

- AMPA receptors - NMDA receptors

Epinephrine

- Another biogenic amine - NOT a common neurotransmitter in the CNS - Major hormone secreted by adrenal medulla

General factors of synaptic strength

- Area of synaptic contact - Enzymatic destruction of neurotransmitter - Geometry of diffusion path (how close are the two neurons) - Neurotransmitter reuptake

Presynaptic factors of synaptic strength

- Availability of neurotransmitter (availability of precursor molecules, amount (or activity) of the rate-limiting enzyme in the pathway for neurotransmitter synthesis) - Axon terminal membrane potential - Axon terminal Ca2+ (more = more synaptic strength) - Activation of membrane receptors on presynaptic terminal (axo-axonic terminals, autoreceptors, other receptors) - Certain drugs and diseases, which act using the above 4 mechanisms

Receptors for neuromodulators

- Bring about changes in metabolic processes in neurons - Such changes can occur over minutes, hours, or even days and include alterations in enzyme activity or, through influences on DNA transcription, in protein synthesis

Amino acid neurotransmitters

- By far the most prevalent neurotransmitters in CNS - Affect virtually all neurotransmitters there

Neuropeptides

- Composed of 2 or more amino acids linked together by peptide bonds - About 100 have been identified - Not all physiological functions are known

Adenosine

- Derived from ATP via extracellular enzymatic activity - Both pre and postsynaptic receptors have been described for adenosine - Functions these substances have in nervous system and other tissued is being researched

Most common biogenic amines

- Dopamine - Norepinephrine - Serotonin - Histamine

How drugs/diseases act on the nervous system

- Drugs act on the nervous system by interfering with or stimulating normal processes in the neuron involved in neurotransmitter synthesis, storage, and receptor activation - Diseases can also affect synaptic mechanisms

Epinephrine/norepinephrine

- Epinephrine/norepinephrine are excitatory - Stimulate fight or flight response - Some antidepressants inhibit MAO

Ethanol and GABA

- Ethanol stimulates GABA synapses and simultaneously inhibits excitatory glutamate synapses - Overall effect is global depression of brain electrical activity

Cannabinoid receptors

- Found throughout CNS and PNS - In pathways regulating many physiological functions including appetite, pain sensation, mood, memory, and locomotor activity - Principle target of THC - Principle psychoactive constituent of cannabis plants

GABA

- Gamma aminobutyric acid - Major inhibitory neurotransmitter in the brain - Classified with the amino acid neurotransmitters because it is a modified form of glutamate - Postsynaptically, GABA may bind to ionotropic or metabotropic receptors

Excitatory postsynaptic potential (EPSP)

- Generated by excitatory chemical synapses - Depolarizing graded potential that decreases in magnitude as it spreads away from the synapse by local current - Only function is to bring the membrane potential of the postsynaptic neuron closer to threshold

Inhibitory postsynaptic potential (IPSP)

- Generated by inhibitory chemical synapses - Hyperpolarizing graded potential that lessens likelihood post synapic cell will depolarize to threshold potential and generate an action potential - Stabilizing

Postsynaptic factors of synaptic strength

- Immediate past history of electrical state of postsynaptic membrane (for example, excitation/inhibition from temporal/spatial summation) - Effects of other neurotransmitters or neuromodulators acting on postsynaptic neuron - Up/down regulation and desensitization of receptors - Certain drugs and diseases

Neuropeptide precursors

- In the cell body, the precursor protein is packaged into vesicles, which are then moved by axonal transport into the terminals or varicosities where the protein is cleaved by specific peptidases - Many of the precursor proteins contain multiple peptides, which may be different or copies of proteins

Purines

- Include ATP and adenosine - Act principally as neuromodulators

Catecholamines

- Include dopamine, norepinephrine, and epinephrine - Contain a catechol ring and an amine group - Formed from the amino acid tyrosine - Subgroup of biogenic amines

Receptors for neurotransmitters

- Influence ion channels that directly affect excitation or inhibition of the postsynaptic cell - These mechanisms operate within milliseconds

Long-term potentiation (LTP) of glutamate

- Involves cooperation of AMPA and NMDA receptors - This mechanism couples frequent activity across a synapse with lasting changes in the strength of signaling across that synapse - Thought to be a cellular process involved in learning and memory

GABA receptors

- Ionotropic receptor increases calcium flux into the cell, resulting in hyperpolarization (an IPSP) of the postsynaptic membrane - In addition to GABA binding site, this receptor has several additional binding sites for other compounds, including steroids, barbiturates, and benzodiazepines

Electrical synapse

- Joined by gap junction - Continuous propagation of AP

Synapse

- Junction between 2 neurons - Excitatory (depolarizing) or inhibitory (hyperpolarizing or stable)

Botox

- Low doses of botulinum toxin (Botox) are injected therapeutically to treat a number of conditions, including facial wrinkles, severe sweating, uncontrollable blinking, misalignment of the eyes, and others.

LSD

- Lysergic acid diethalymide - Stimulates the 5-HT2A subtype of serotonin receptor in the brain, causing intense visual hallucinations

Glycine

- Major neurotransmitter released from inhibitory interneurons in the spinal cord and brainstem - Binds to ionotropic receptors on postsynaptic cells that allow Ca2+ to enter

Neuroeffector junctions

- Many neurons of PNS synapse at these junctions on muscle, glands, and other cells - Act similarly to synapses between neurons

2 types of glutamate receptors

- Metabotropic receptors (g protein-coupled) - Ionotropic receptors (the vast majority)

Chemical synapse

- More common - Ends in axon terminal with synaptic vesicles

Peptidergic

- Neurons that release one or more of the peptide neurotransmitters are collectively called peptidergic - Neuropeptides are co-secreted with another type of neurotransmitter and act as neuromodulators

Strychnine

- Neurotoxin - Antagonist of glycine receptor - Victims experience hyperexcitability throughout the nervous system - Leads to convulsions, spastic contraction of skeletal muscles, and ultimately death due to impairment of respiratory muscles

Neuroeffector junction steps

- Neurotransmitter is released from efferent neuron upon AP arrival - Diffuses to surface of effector cell - Binds to receptor cell's plasma membrane - Receptors on effector cell may be ionotropic or metabotropic

Examples of gases

- Nitric oxide - Carbon monoxide - Hydrogen sulfide

Gases

- Not released by exocytosis of presynaptic vesicles - Do not bind to postsynaptic plasma membrane - Produced by enzymes in the axon terminals (in response to Ca2+ entry) and simply diffuse from their origin sites into ICF of other neurons/effector cells, where they bind to and activate proteins

Neuromodulators

- Often modify postsynaptic cell's response to specific neurotransmitters - Amplify or dampen effectiveness of ongoing synaptic activity - May change presynaptic cell's synthesis, release, reuptake, or metabolism of a neurotransmitter

Divergence

- One neuron sends signal to multiple neurons - Info diverges

ATP

- Present in all presynaptic vesicles - Coreleased with one or more other neurotransmitters in response to Ca2+ influx into terminal

Convergence

- Several neurons all act one one neuron - Info converges

Lipids

- Some membrane phospholipid-derived substances are more important for synaptic signaling - Most commonly act as neuromodulators - Many are eicosanoids

Benzodiazepine drugs

- Such as alprazolam (Xanax) and diazepam (Valium) - Reduce anxiety, guard against seizures, and induce sleep by increasing Ca flux into the GABA receptor

Selective serotonin reuptake inhibitors

- Such as paroxetine (Paxil) - Aid in treatment of depression by inactivating the presynaptic membrane 5HT transporter, which mediates the reuptake of serotonin

Clostridium tetani

- The bacillus Clostridium tetani produces a toxin (tetanus toxin), which is a protease that destroys SNARE proteins in the presynaptic terminal so that fusion of vesicles with the membrane is prevented, inhibiting neurotransmitter release. - Ultimately, this causes excess muscle contraction and a rigid or spastic paralysis.

Clostridium botulinum bacilli

- Toxins of the Clostridium botulinum bacilli, which cause botulism, also block neurotransmitter release from synaptic vesicles by destroying SNARE proteins. - They target excitatory synapses that activate skeletal muscles; botulism is characterized by reduced muscle contraction, or a flaccid paralysis.

Adenergic receptors

- Utilized by neurotransmitters norepinephrine (NE) and epinephrine (Epi) - NE found in CNS and PNS - Epi mainly found in PNS - All are metabotropic, and thus use second messengers to transfer a signal from the surface of the cell to the cytoplasm

High doses of ethanol

- Very high doses of ethanol are sometimes fatal - Due to suppression of brainstem centers responsible for regulating cardio and respiratory systems

A drug might...

-Increase leakage of neurotransmitter from vesicle to cytoplasm, exposing it to enzyme breakdown - Increase transmitter release into cleft - Block transmitter release - Inhibit transmitter synthesis - Block cleft or intracellular enzymes that metabolize transmitter - Bind to receptor to block (antagonist) or mimic (agonist) transmitter action - Inhibit or stimulate second messenger activity within postsynaptic cell

Effects of arising blood-alcohol content

-Progressive reduction in cognitive ability - Sensory perception inhibition (particularly hearing and balance) - Loss of motor coordination - Impaired judgement - Memory loss - Unconsciousness

LTP steps

1. High-frequency action potentials in presynaptic cell 2. Glutamate is released 3. Glutamate binds to both channels 4. Na+ entry depolarizes the cell by 20-30 mV 5. Depolarization drives Mg2+ ion out of pore 6. Ca2+ entry through NMDA receptor activates second messenger systems to increase sensitivity 7. Long-lasting increase in glutamate receptors and sensitivity 8. Long-lasting increase in presynaptic glutamate synthesis and release via retrograde signals

Methods of transmitter removal

1. Uptake of receptor 2. Reuptake by neuron that released it 3. Diffusion out of synaptic cleft 4. Enzymatic inactivation

ACh binds to...

ACh binds to muscarinic (g protein-coupled) or nicotinic (ligand-gated ion channel) receptors

ACh synthesis and storage

ACh is synthesized from choline and acetyl coenzyme A in cytoplasm of synaptic terminals, and is stored in synaptic vesicles

Alpha-adrenergic receptors

Alpha 1 and alpha 2

Distribution of serotonin

Approximately 90% of serotonin is in the digestive system, 8% is in the blood platelets and immune cells, and only 1% is in the brain

Amino acids at excitatory synapses

Aspartate and glutamate

Beta-adrenergic receptors

Beta 1, beta 2, and beta 3

Monoamine oxidase (MAO)

Break down catecholamine neurotransmitters in the ECF and axon terminals

Degradation of ACh

Degradation of ACh occurs rapidly due to action of enzyme acetyl cholinisterase, which is located on the pre and post synaptic membranes

Examples of neuropeptides

Endogenous opioids: - Beta-endorphin - Dynorphins - Enkephalins - Morphine and codeine are synthetic opioids that are used as analgesics (pain reducers)

Glutamate

Estimated to be the primary neurotransmitter at 50% of the excitatory synapses in the CNS

Serotonergic pathways

Function in the regulation of food intake, reproductive behavior, and emotional states such as mood and anxiety

Amino acids at inhibitory synapses

Glycine and GABA

Norepinephrine

Important neurotransmitter in CNS and PNS

Histamine

Made from amino acid histidine

Acetylcholine (ACh)

Major neurotransmitter in PNS at neuromuscular junctions and in the brain

Cholinergic neurons

Neurons that release ACh

Functional difference between neurotransmitters and neuromodulators

Neurotransmitters are involved in rapid communication, whereas neuromodulators tend to be associated with slower events such as learning, development, and motivational states

Normal glycine function

Normal function of glycinergic neurons is essential for maintaining inhibitory activity in spinal cord integrating centers that regulate skeletal muscle contraction

Serotonin

Produced from the essential amino acid tryptophan

GABA neurons

Small interneurons that dampen activity within neural circuits

Biogenic amines

Small, charged molecules that are synthesized from amino acids

Ethanol

Synapses that use GABA are among the many targets of ethanol found in alcoholic beverages

Catecholamine biosynthetic pathway

Tyrosine --> L-dopa --> dopamine --> norepinephrine --> epinephrine